Cardiovascular disease (CVD) is a major cause of death and disability in the United States. An individual's risk for CVD contains a substantial genetic component. Along with being highly heritable, plasma lipid concentrations are also strong determinants of CVD risk. Recently, there have been several large, concerted efforts to investigate the genetics of plasma lipid levels and CVD in population based studies. However successful these studies have been, approximately 70% of the genetic variance in plasma lipid levels remains unexplained. A popular hypothesis states that rare genetic variants that were un-assayed in previous studies may account for a significant portion of this unexplained variation. Sex steroid hormones and their receptors are also critical determinants of plasma lipid levels and CVD risk. An important unresolved question is whether genetic variability influences the effect of estrogen and/or progesterone in modifying lipid levels and risk for CVD. We will use genetic data, health histories, lipid concentrations, and data from a randomized clinical trial on hormone-therapy (HT) from the Women's Health Initiative (WHI) to: (1) identify rare genetic variants associated with plasma lipid levels in European America (EA) and African American (AA) postmenopausal women; and (2) identify rare genetic variants that interact with HT to modify plasma lipid levels and risk for CVD in EA and AA postmenopausal women. Information generated from this study will be critical in determining the impact of genetic variants on women's health and to prioritize them for intervention studies aimed to maximize overall clinical benefit of HT and minimize their associated cardiovascular risk. Findings may also provide valuable insights into disease pathways and mechanisms, and identify novel targets for screening, prevention, and treatment of dyslipidemia and CVD in postmenopausal women.